| Immunoglobulin-like receptor | |
|---|---|
 Schematic diagram showing Fc receptor interaction with an antibody-coated microbial pathogen | |
| Identifiers | |
| Symbol | Fc receptor |
| Membranome | 10 |
Inimmunology, anFc receptor is aprotein found on thesurface of certaincells – including, among others,B lymphocytes,follicular dendritic cells,natural killer cells,macrophages,neutrophils,eosinophils,basophils, humanplatelets, andmast cells – that contribute to the protective functions of theimmune system.Its name is derived from its binding specificity for a part of anantibody known as theFc (fragment crystallizable) region. Fc receptors bind to antibodies that are attached to infected cells or invadingpathogens. Their activity stimulatesphagocytic orcytotoxic cells to destroymicrobes, or infected cells by antibody-mediatedphagocytosis orantibody-dependent cell-mediated cytotoxicity. Someviruses such asflaviviruses use Fc receptors to help them infect cells, by a mechanism known asantibody-dependent enhancement of infection.[1]
There are several different types of Fc receptors (abbreviated FcR), which are classified based on thetype of antibody that they recognize. The Latin letter used to identify a type of antibody is converted into the corresponding Greek letter, which is placed after the 'Fc' part of the name. For example, those that bind the most common class of antibody,IgG, are called Fc-gamma receptors (FcγR), those that bindIgA are called Fc-alpha receptors (FcαR) and those that bindIgE are called Fc-epsilon receptors (FcεR). The classes of FcRs are also distinguished by the cells that express them (macrophages, granulocytes, natural killer cells, T and B cells) and the signalling properties of each receptor.[2]
All of the Fcγ receptors (FcγR) belong to theimmunoglobulin superfamily and are the most important Fc receptors for inducingphagocytosis ofopsonized (marked) microbes.[3] This family includes several members, FcγRI (CD64), FcγRIIA (CD32), FcγRIIB (CD32), FcγRIIIA (CD16a), FcγRIIIB (CD16b), which differ in their antibodyaffinities due to their differentmolecularstructure.[4] For instance, FcγRI binds to IgG more strongly than FcγRII or FcγRIII does. FcγRI also has anextracellular portion composed of threeimmunoglobulin (Ig)-like domains, one more domain than FcγRII or FcγRIII has. This property allows FcγRI to bind a sole IgG molecule (ormonomer), but all Fcγ receptors must bind multiple IgG molecules within animmune complex to be activated.[5]
The Fc-gamma receptors differ in their affinity for IgG and likewise the different IgG subclasses have unique affinities for each of the Fc gamma receptors.[6] These interactions are further tuned by the glycan (oligosaccharide) at position CH2-84.4 of IgG.[6] For example, by creating steric hindrance,fucose containing CH2-84.4 glycans reduce IgG affinity for FcγRIIIA.[6] In contrast, G0 glycans, which lackgalactose and terminate instead with GlcNAc moieties, have increased affinity for FcγRIIIA.[6]
Another FcR is expressed on multiple cell types and is similar in structure toMHC class I. This receptor also binds IgG and is involved in preservation of this antibody.[7] However, since this Fc receptor is also involved in transferring IgG from a mother either via theplacenta to herfetus or inmilk to her sucklinginfant, it is called theneonatal Fc receptor (FcRn).[8][9] Recently, research suggested that this receptor plays a role in the homeostasis of IgG serum levels.
Only one Fc receptor belongs to the FcαR subgroup, which is called FcαRI (or CD89).[10] FcαRI is found on the surface ofneutrophils, eosinophils, monocytes, some macrophages (includingKupffer cells), and somedendritic cells.[10] It is composed of two extracellular Ig-like domains, and is a member of both theimmunoglobulin superfamily and the multi-chain immune recognition receptor (MIRR) family.[3] It signals by associating with two FcRγ signaling chains.[10] Another receptor can also bind IgA, although it has higher affinity for another antibody calledIgM.[11] This receptor is called the Fc-alpha/mu receptor (Fcα/μR) and is atype I transmembrane protein. With one Ig-like domain in its extracellular portion, this Fc receptor is also a member of the immunoglobulin superfamily.[12]
Two types of FcεR are known:[3]
| Receptor name | Principal antibody ligand | Affinity for ligand | Cell distribution | Effect following binding to antibody |
|---|---|---|---|---|
| FcγRI (CD64) | IgG1 and IgG3 | High (Kd ~ 10−9 M) | Macrophages Neutrophils Eosinophils Dendritic cells | Phagocytosis Cell activation Activation of respiratory burst Induction of microbe killing |
| FcγRIIA (CD32) | IgG | Low (Kd > 10−7 M) | Macrophages Neutrophils Eosinophils Platelets Langerhans cells | Phagocytosis Degranulation (eosinophils) |
| FcγRIIB1 (CD32) | IgG | Low (Kd > 10−7 M) | B Cells Mast cells | No phagocytosis Inhibition of cell activity |
| FcγRIIB2 (CD32) | IgG | Low (Kd > 10−7 M) | Macrophages Neutrophils Eosinophils | Phagocytosis Inhibition of cell activity |
| FcγRIIIA (CD16a) | IgG | Low (Kd > 10−6 M) | NK cells Macrophages (certain tissues) | Induction ofantibody-dependent cell-mediated cytotoxicity (ADCC) Induction of cytokine release by macrophages |
| FcγRIIIB (CD16b) | IgG | Low (Kd > 10−6 M) | Eosinophils Macrophages Neutrophils Mast cells Follicular dendritic cells | Induction of microbe killing |
| FcεRI | IgE | High (Kd ~ 10−10 M) | Mast cells Eosinophils Basophils Langerhans cells Monocytes | Degranulation Phagocytosis |
| FcεRII (CD23) | IgE | Low (Kd > 10−7 M) | B cells Eosinophils Langerhans cells | Possible adhesion molecule IgE transport across human intestinal epithelium Positive-feedback mechanism to enhance allergic sensitization (B cells) |
| FcαRI (CD89) | IgA | Low (Kd > 10−6 M) | Monocytes Macrophages Neutrophils Eosinophils | Phagocytosis Induction of microbe killing |
| Fcα/μR (CD351) | IgA and IgM | High for IgM, Mid for IgA | B cells Mesangial cells Macrophages | Endocytosis Induction of microbe killing |
| FcμR[17] | IgM | (unknown) | Human FcμR is predominantly expressed by lymphocytes, but not by phagocytes[18] | function has not been fully elucidated / diverse[19] |
| FcRn | IgG | high in acidic cellular endosomes low in pH neutral extracellular environment | Monocytes Macrophages Dendritic cells Epithelial cells Endothelial cells Hepatocytes | Transfers IgG from a mother to fetus through the placenta Transfers IgG from a mother to infant in milk Protects IgG from degradation Transfers IgG across endothelial/epithelial layers |
Fc receptors are found on a number of cells in the immune system includingphagocytes likemacrophages andmonocytes,granulocytes likeneutrophils andeosinophils, andlymphocytes of theinnate immune system (natural killer cells) oradaptive immune system (e.g.,B cells).[20][21][22]They allow these cells to bind to antibodies that are attached to the surface of microbes or microbe infected cells, helping these cells to identify and eliminatemicrobialpathogens. The Fc receptors bind the antibodies at theirFc region (or tail), an interaction that activates the cell that possesses the Fc receptor.[23] Activation of phagocytes is the most common function attributed to Fc receptors. For example, macrophages begin toingest and kill anIgG-coatedpathogen byphagocytosis following engagement of their Fcγ receptors.[24] Another process involving Fc receptors is calledantibody-dependent cell-mediated cytotoxicity (ADCC). During ADCC, FcγRIII receptors on the surface of natural killer (NK) cells stimulate the NK cells to release cytotoxic molecules from theirgranules to kill antibody-covered target cells.[25]FcεRI has a different function. FcεRI is the Fc receptor ongranulocytes, that is involved inallergic reactions and defense against parasiticinfections. When an appropriate allergic antigen or parasite is present, the cross-linking of at least twoIgE molecules and their Fc receptors on the surface of a granulocyte will trigger the cell to rapidly release preformed mediators from its granules.[3]
Fc gamma receptors belong to the group ofnon-catalytic tyrosine-phosphorylated receptors which share a similar signalling pathway involving phosphorylation of tyrosine residues.[26] The receptors generate signals within their cells through an important activation motif known as animmunoreceptor tyrosine-based activation motif (ITAM).[27] An ITAM is a specific sequence ofamino acids (YXXL) occurring twice in close succession in theintracellular tail of a receptor. Whenphosphate groups are added to thetyrosine (Y) residue of the ITAM by membrane-anchoredenzymes of theSrc kinase family, asignaling cascade is generated within the cell. Thisphosphorylation reaction typically follows interaction of an Fc receptor with itsligand. An ITAM is present in the intracellular tail of FcγRIIA, and its phosphorylation induces phagocytosis in macrophages. FcγRI and FcγRIIIA do not have an ITAM but can transmit an activating signal to their phagocytes by interacting with another protein that does. Thisadaptor protein is called the Fcγ subunit and, like FcγRIIA, contains the two YXXL sequences that are characteristic of an ITAM.
The presence of only one YXXL motif is not sufficient to activate cells, and represents a motif (I/VXXYXXL) known as animmunoreceptor tyrosine-based inhibitory motif (ITIM). FcγRIIB1 and FcγRIIB2 have an ITIM sequence and are inhibitory Fc receptors; they do not induce phagocytosis. Inhibitory actions of these receptors are controlled by enzymes that remove phosphate groups from tyrosine residues; thephosphatasesSHP-1 andSHIP-1 inhibit signaling by Fcγ receptors.[28] Binding of ligand to FcγRIIB leads to phosphorylation of the tyrosine of the ITAM motif. This modification generates the binding site for the phosphatase, a SH2 recognition domain. The abrogation of ITAM activation signaling is caused by inhibition of protein tyrosine kinases of Src family, and by hydrolyzing the membrane PIP3 interrupting the further downstream signaling by the activating receptors, such as activating FcγRs, TCR, BCR and cytokine receptors (e.g. c-Kit).[29]
The negative signaling by FcγRIIB is mainly important for regulation of activated B cells. The positive B cell signaling is initiated by binding of foreign antigen to surface immunoglobulin. The same antigen-specific antibody is secreted and it can feedback-suppress, or promote negative signaling. This negative signaling is being provided by FcγRIIB.:[30] Experiments using B cell deletion mutants and dominant-negative enzymes have firmly established an important role for SH2-domain-containing inositol 5-phosphatase (SHIP) in negative signaling. Negative signaling through SHIP appears to inhibit theRas pathway through SH2 domain competition with Grb2 and Shc and may involve consumption of intracellular lipid mediators that act as allosteric enzyme activators or that promote entry of extracellular Ca2+.[31]
WhenIgG molecules, specific for a certain antigen or surface component, bind to the pathogen with theirFab region (fragment antigen binding region), their Fc regions point outwards, in direct reach ofphagocytes. Phagocytes bind those Fc regions with their Fc receptors.[24] Many low affinity interactions are formed between receptor and antibody that work together to tightly bind the antibody-coated microbe. The low individual affinity prevents Fc receptors from binding antibodies in the absence of antigen, and therefore reduces the chance of immune cell activation in the absence of infection. This also preventsagglutination (clotting) ofphagocytes by antibody when there is no antigen. After a pathogen has been bound, interactions between the Fc region of the antibody and the Fc receptors of the phagocyte results in the initiation ofphagocytosis. The pathogen becomes engulfed by the phagocyte by an active process involving the binding and releasing of the Fc region/Fc receptor complex, until thecell membrane of the phagocyte completely encloses the pathogen.[32]
The Fc receptor on NK cells recognize IgG that is bound to the surface of a pathogen-infected target cell and is called CD16 or FcγRIII.[33] Activation of FcγRIII by IgG causes the release ofcytokines such asIFN-γ that signal to other immune cells, and cytotoxic mediators likeperforin andgranzyme that enter the target cell and promote cell death by triggeringapoptosis. This process is known asantibody-dependent cell-mediated cytotoxicity (ADCC). FcγRIII on NK cells can also associate with monomeric IgG (i.e., IgG that is not antigen-bound). When this occurs, the Fc receptor inhibits the activity of the NK cell.[34]
IgE antibodies bind toantigens ofallergens. These allergen-bound IgE molecules interact with Fcε receptors on the surface ofmast cells. Activation of mast cells following engagement of FcεRI results in a process calleddegranulation, whereby the mast cell releases preformed molecules from itscytoplasmic granules; these are a mixture of compounds includinghistamine,proteoglycans, andserine proteases.[35] Activated mast cells also synthesize and secretelipid-derived mediators (such asprostaglandins,leukotrienes, andplatelet-activating factor) and cytokines (such asinterleukin 1,interleukin 3,interleukin 4,interleukin 5,interleukin 6,interleukin 13,tumor necrosis factor-alpha,GM-CSF, and severalchemokines.[36][37] These mediators contribute toinflammation by attracting otherleukocytes.
Large parasites like thehelminth (worm)Schistosoma mansoni are too large for ingestion by phagocytes. They also have an external structure called anintegument that is resistant to attack by substances released by macrophages and mast cells. However, these parasites can become coated with IgE and recognized by FcεRII on the surface ofeosinophils. Activated eosinophils release preformed mediators such asmajor basic protein, andenzymes such asperoxidase, against which helminths are not resistant.[38][39] The interaction of theFcεRII receptor with the Fc portion of helminth bound IgE causes the eosinophil to release these molecules in a mechanism similar to that of the NK cell during ADCC.[40]
CD4+ T cells (mature Th cells) provide help to B cells that produce antibodies. Several subsets of activated effector CD4+ T cells are observed in disease pathology. Earlier studies summarized by Sanders and Lynch in 1993 suggested critical roles for FcRs in CD4+ T cell mediated immune responses and proposed the formation of a joint signaling complex among FcRs and TCR on the cell surface.[41][42][43][44] Chauhan and coworkers reported the colocalization of the labeled ICs with the CD3 complex on activated CD4+ T cell surface, which thus suggest the coexistence of FcRs together with TCR complex.[45] Both of these receptors are observed forming an apical structure on the membrane of activated CD4+ T cells, suggesting the lateral movement of these receptors.[46] Co-migration of FcRs with TCR and BCR complex is observed on the cells surface and T:B cell cytoconjugates show this coexistence at the point of contact.[47] An earlier review suggested that the expression of FcRs on CD4+ T cells is an open question.[48] This established the current paradigm that T cells do not express FcRs and these findings were never challenged and experimentally tested.[49] Chauhan and coworkers showed binding of immune complexes (ICs), the FcR ligand to activated CD4+ T cells.[49] CD16a expression is induced in the activated human naïve CD4+ T cells, which express CD25, CD69, and CD98 and ligation to ICs leads to generation of effector memory cells.[50] CD16a signaling is mediated by phosphorylation of Syk (pSyk).[50][51][52]
A study now suggests induced expression of CD32a upon activation of human CD4+ T cells, similar to CD16a.[51][53] CD32a expression on CD4+ T cells was also suggested by three independent studies from HIV-1 researchers. The expression of CD16a and CD32a in a subset of activated CD4+ T cells is now confirmed.[51][53] FcRs on the cell surface upon binding to ICs composed of nucleic acids trigger cytokine production and upregulate nucleic acid sensing pathways. FcRs are present both on the cell surface and in the cytosol. CD16a signaling upregulate the expression of nucleic acid sensing toll-like receptors and relocate them to cell surface.[50][54] CD16a is a new costimulatory signal for human CD4+ T cells, which successfully substitute the CD28 requirement during autoimmunity.[55] In an autoimmune background CD4+ T cells bypass the requirement of CD28 cosignaling to become fully activated.[55] Furthermore, the blockade of CD28 cosignaling does not inhibit the development of TFH cells, a key subset for the generation of autoantibody producing autoreactive plasma B cells.[56] A balance among costimulatory and inhibitory signals is required for immune homeostasis. Excessive costimulation and/or insufficient co-inhibition leads to the tolerance-breakdown and autoimmunity. CD16a mediated costimulation provides a positive signal in the activated CD4+ T cells and not in the quiescent cells which lack FcγR expression.[51]